TW201339139A - Inhibitors of beta-secretase - Google Patents

Abstract

Thepresent invention relates to spirocyclic acylguanidines and their use as inhibitors of the β -secretase enzyme (BACE1) activity, pharmaceutical compositions containing the same, and methods of using the same as therapeutic agents in the treatment of neurodegenerative disorders, disorders characterized by cognitive decline, cognitive impairment, dementia and diseases characterized by production of β -amyloid aggregates.

Description

--secretase inhibitor [related application]

The present application claims the benefit of U.S. Provisional Application Serial No. 61/606,786, filed on March 5, 2012, the entire disclosure of which is incorporated herein by reference.

The present invention relates to a spirocyclic guanidine group and its use as an inhibitor of β-secretase (BACE1) activity, a pharmaceutical composition containing the same, and a use thereof as a therapeutic agent for treating a neurodegenerative disorder characterized by cognitive decline, Cognitive disorders, conditions and characteristics of dementia are methods of producing diseases of beta-like starch deposition or neurofibrillary tangles.

The deposition of β-type starch (also referred to herein as "Abeta" or "A β") and neurofibrillary tangles are two major pathological features associated with Alzheimer's disease (AD), Az Hermite includes genetically related early-onset family forms due to starch-like precursor proteins (APP), presenilin 1 and 2 mutations, and late-onset sporadic AD. Clinically, AD characteristics are memory, cognition, reasoning, judgment, and directional loss. As the disease progresses, it also affects exercise, perception, and language ability until multiple cognitive impairments occur. These cognitive losses occur gradually, but typically result in severe injury and eventually death within 4-12 years. The β-type starch deposition is mainly the aggregation of A β peptide, and the A β peptide is the product of APP proteolysis. More specifically, the Aβ peptide is cleaved by APP at the C-terminus by one or more γ-secretases and at the N-terminus by β-secretase (BACE1) (also known as aspartame thiol protease and memapsin2). This is part of the beta-amyloid pathway.

BACE activity is directly related to the production of A beta peptide from APP, and studies have increasingly indicated that inhibition of BACE inhibits the production of A beta peptide.

Amyloid plaques and vascular amyloplasty are also the 21st chromosome trisomy (Down Syndrome), Dutch amyloid hereditary cerebral hemorrhage (HCHWA-D) and other neurodegenerative Brain characteristics of patients with symptoms. Neurofibrillary tangles are also present in other neurodegenerative disorders, including those induced by dementia.

Recently, it has been reported that Aβ is involved in the apoptosis of retinal ganglion cells (RGC) in glaucoma, evidenced by the increase in Aβ expression in the RGCs mediated by caspase-3-mediated abnormal starch-like precursor protein treatment and experimental glaucoma. The vitreous A beta content in patients with glaucoma is reduced (consistent with retinal A beta deposition). Starch-like deposition is also associated with macular degeneration in patients with age-related macular degeneration (AMD) and AMD animal models.

WO 2010/021680, WO 2011/106414 and WO 2010/105179 disclose spirocyclic indenyl groups having a spirocyclic skeleton as a β-secretase inhibitor.

The present invention provides a compound which is a BACE1 inhibitor and is used as a therapeutic agent for treating a disease or condition characterized by a β-based starch deposition or an elevated β-based starch content in a patient. The disclosed BACE1 inhibitors are not only highly potent BACE1 enzyme inhibitors (assay 1) but also: (1) highly potent inhibitory activity in the cellular A beta assay (assay 2), and (2) selective counteracting in cell assays Cardiac hERG channels (assay 3), and (3) a lower propensity to cause phospholipidosis in cellular phospholipidosis assays (assay 4).

Accordingly, the present invention provides compounds which exhibit a combination of high BACE1 inhibitor potency, high selectivity to cardiac hERG channels, and low phospholipidosis activity.

A specific example of the present invention is a compound represented by a structural formula selected from the group consisting of: Or a pharmaceutically acceptable salt of any of the foregoing compounds. The foregoing compounds are referred to herein as "compounds of the invention."

Another specific example of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

Another embodiment of the invention is a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Another embodiment of the invention is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a BACE1-mediated condition or disease in an individual.

Another embodiment of the invention is the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a BACE1-mediated condition in an individual.

Another embodiment of the invention is a pharmaceutical composition comprising a compound of the invention for use in treating a BACE1-mediated condition or disease in an individual.

Another embodiment of the invention is a method of treating an individual having a BACE1-mediated disease or condition comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is an intermediate for the preparation of a compound of the invention. These intermediates are represented by a structural formula selected from the following: Or a salt of any of the foregoing compounds.

The compounds of the present invention exhibit potent activity against BACE1 enzyme and Aβ formation, as well as selectivity to hERG channels and a lower propensity to cause phospholipidosis. For example, the compounds of the present invention exhibit IC ₅₀ <15 nM inhibition of BACE1, IC ₅₀ <cell A β 2 nM suppressed the generation, at 10 μM <50% of hERG inhibition effect and a first concentration (FEC)> 150 μM Phospholipid disease. The nature of such combinations renders the compounds of the invention useful in the treatment of pathological conditions in humans, in particular, in the treatment of Alzheimer's disease as well as other conditions and diseases mediated by BACE1.

Inhibition of hERG (human ether-à-go-go related gene) channels by foreign organisms as determined by Sanguinetti et al. (1995, Cell, Apr. 21, 81(2): 299-307) and many subsequent evidences Cardiac repolarization is associated with an increased risk of specific polymorphic ventricular tachycardia and torsades de pointes. In order to avoid this risk as early as possible, it is customary to use the heterologous expression of the hERG channel to screen for hERG interactions in the in vitro system and this type of assay is also ICH guidelines S7B (International Conference on Harmonization (2005): ICH Topic S 7 B The Nonclinical Evaluation of the Potential for delayed Ventricular Repolarization; (QT Interval Prolongation) by Human Pharmaceuticals (www.ich.org/products/guidelines/safety/article/safety-guidelines.html)) The importance of recommending a later preclinical candidate profile section. Thus, low hERG channel inhibition, such as shown by the compounds of the invention, is highly desirable for treatment.

Phospholipidopathy is a lipid storage disorder in which excess phospholipids accumulate in cells. Drug-induced phospholipidosis is an adverse drug reaction. Therefore, in order to avoid harmful side effects, compounds having the possibility of low phospholipidosis are preferred for human therapeutic use. The information provided in Table 1 below shows that the compounds of the invention have the following combinations: potent BACE1 cell activity, selectivity to cardiac hERG, and low propensity to cause phospholipid disease. The compounds exemplified in the letters WO 2010/021680 and WO 2010/105179 do not have a combination of the desired characteristics. In addition, Table 2 provides information on the display ₅₀ BACE1 enzyme assay and inhibition values specific compounds of the present invention is also a cell A β assay relative to a particular comparison of the compound in WO 2010/105179 having a significantly lower IC.

Terms that are not explicitly defined herein should be given to those skilled in the art in light of the disclosure and context. However, as used in the specification, the following terms have the specified meaning and the following convention should be adhered to unless otherwise stated.

When the compounds of the invention are depicted by name or structure without indicating all tautomeric forms, it is to be understood that the compounds and their pharmaceutically acceptable salts will encompass all tautomers.

When a compound of the invention is depicted by name or structure without indicating stereochemistry, it is to be understood that the compound and its pharmaceutically acceptable salts will encompass all stereoisomers, optical isomers and geometric isomers thereof (eg, , enantiomers, diastereomers, E/Z isomers, etc.) and racemates, as well as mixtures of individual enantiomers, mixtures of diastereomers or in any ratio A mixture of the foregoing forms.

When stereoisomers, optical isomers or geometric isomers are depicted by name or structure, it is to be understood that the stereoisomers, optical isomers or geometric isomers named or depicted are stereo The isomers, optical isomers and/or geometric isomers are at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt% or 99.9% pure. Stereoisomer purity, optical isomeric purity, and geometric isomeric purity are determined by the weight of the stereoisomers, optical isomers, and geometric isomers in the mixture divided by all stereoisomers, optics in the mixture. The total weight of the isomers and geometric isomers is determined.

When a compound of the present invention or a pharmaceutically acceptable salt thereof is named or depicted by a structure, it is understood that the solvate, hydrate and anhydrous form of the compound and the solvate or hydrate of the pharmaceutically acceptable salt thereof And anhydrous forms are included in the present invention. "Solvate" refers to a crystalline form in which a solvent molecule is incorporated into a crystal lattice during crystallization. The solvate may include water or a non-aqueous solvent such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. A solvate in which water is a solvent molecule incorporated into a crystal lattice is typically referred to as a "hydrate." Hydrates include stoichiometric hydrates and compositions containing variable amounts of water. "Anhydrous form" means a compound that is solvent-free or water-free or substantially solvent-free or water-incorporated into the crystal structure (eg, a solvent or water ratio of less than 1:10; 1:20; 1:100 or 1:200 mole ratio) Compound).

salt

In this context, the term "pharmaceutically acceptable" is used to refer to the use of humans and animal tissues in the context of sound medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications. A compound/material, composition, and/or dosage form of a benefit/risk ratio. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound modified by the parent compound by the preparation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like Things. For example, the salts include salts from the group consisting of ammonia, L-arginine, betaine, benzidine, benzathine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine. (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-reduced glucosamine, Hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrogen ginseng (ethanol), tromethamine, zinc hydroxide, Acetic acid, 2,2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-ethylammonium- Benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, citric acid, lauryl sulfate, ethane-1,2 -disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, D-glucose heptanoic acid, D - gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, caproic acid, hippuric acid, hydrobromic acid, hydrochloric acid , isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactose Acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, Diacid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, hydrazine Diacid, stearic acid, succinic acid, sulfuric acid, citric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Other pharmaceutically acceptable salts can come from Cationic formation of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like (see also Pharmaceutical salts, Berge, SM et al, J. Pharm. Sci., (1977), 66, 1- 19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic moiety or an acidic moiety by a conventional chemical method. In general, the salts can be obtained by reacting the free acid or free base forms of such compounds with a suitable amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or Prepared by reaction in acetonitrile or a mixture thereof.

Salts (e.g., trifluoroacetate) other than those described above for use in purifying or isolating the compounds of the invention also form part of the invention.

Biological data

BACE1 verification (certification 1)

The inhibitory activity of compounds of BACE1 activity by fluorescence using commercially available assay quenched by mass ^{HiLyte Fluor TM 488-Glu-Val} -Asn-Leu-Asp-Ala-Glu-Phe-Lys- (QXL TM 520) -OH ( SEQ ID NO: 1) AnaSpec, San Jose, CA) , and the myc-his-tag fusion and secreted from HEK293 BACE _ect cells / cut into OptiMEM ^TM (Invitrogen) in the human β- -secretase BACEl (amino acids 1- 454) to assess. The substrate was dissolved in DMSO at 1 mg/ml.

Characterization in OptiMEM containing BACE1 extracellular domain (supernatant collected by 24 hours and removing cell debris by centrifugation), 25 μl of water containing the desired concentration of test compound and 2% DMSO, 1 μM substrate, 20 mM NaOAc, pH 4.4 and 0.04% Triton-X100 was carried out in a 384-well plate with a total assay volume of 50 μl. Generally, adding 25 μl compound dilution to the plates, followed by the addition BACE1 10 μl 1:10 diluted in water containing OptiMEM ^TM and 0.2% Triton X-100 in. The reaction was initiated by the addition of 15 μl of a buffered NaOAc buffer. And the reaction was incubated at Envision ^® ex Multilabel reader (Perkin Elmer) at room temperature (dark): 485 nm, em: 538 nm recorded in the form of kinetic cleavage mass by 60 minutes. Each plate includes a blank well containing no enzyme.

In all 384 wells, the fluorescence intensity was regressed over time to derive the reaction rate. These velocities were used as a percentage control calculation using 0% of the uninhibited control group containing 1% DMSO as 100% and in the absence of enzyme. By using a control assay probe fitting percentage of test compound concentration ₅₀ values _were calculated IC.

Based on H4-APPwt cell assay (assay 2)

In the assay to monitor the production of Aβ 1-x peptide in the H4 glioma cell line (ATCC, Cat. No. HTB-148) stably expressing human APP, an immunoassay such as AlphaLISA (PerkinElmer, Cat. No. AL288) was used. The cellular potency of the compounds of the invention was assessed. The test compound was dissolved in DMSO and pre-diluted in medium (DMEM containing 10% FBS and 1% penicillin/streptomycin) to achieve twice the final concentration of the compound in the assay. An equal volume of 2 x test compound solution and cell suspension was added to a 96-well culture plate such that each well contained approximately 10,000 cells in a final volume of 200 μl. The final concentration of DMSO in the assay was 0.2%. The plates were incubated for 5 hours at 37 ° C under 5% CO 2 to allow cells to adhere to the bottom of the well in the presence of test compounds. The medium was removed and replaced with fresh medium containing the same final concentration of test compound. The plates were incubated at 37 ° C for 18 hours under 5% CO ₂ . The concentration of Ab1-x was determined using an AlphaLISA immunoassay (PerkinEImer, Cat. No. AL288) following the manufacturer's protocol. The concentration of Aβ 1-x in wells containing DMSO or 10 μM β-secretase inhibitor (BACE inhibitor IV, EMD Bioscience, Cat. No. 565788) was used as the unsuppressed and background control group to calculate the test compound. Percent inhibition value in each well. These percent inhibition values using a four-parameter curve fit with respect to compound concentration regression, and IC ₅₀ values (concentration of compound was observed 50% inhibition) is calculated as the compound concentration corresponding to the inflection point on the curve.

hERG channel verification (test 3)

cell:

HEK (human fetal kidney) 293 cells were stably transfected with hERG cDNA.

Straws and solutions:

The cells were plated with a bath solution containing (mM): NaCl (137), KCl (4.0), MgCl ₂ (1.0), CaCl ₂ (1.8), glucose (10), HEPES (10), using NaOH to pH 7.4. A diaphragm pipette was fabricated from a borosilicate glass tube using a horizontal puller and contained (mM): potassium aspartate (130), MgCl ₂ (5.0), EGTA (5.0), K ₂ ATP (4.0), HEPES (10.0) was filled with a pipette solution of KOH reaching pH 7.2. The resistance of the microelectrode is in the range of 2 to 5 MΩ.

Stimulus and record:

The membrane current was recorded using an EPC-10 patch clamp amplifier and a PatchMaster software. The hERG-mediated membrane current was recorded at 35 ° C using a whole cell configuration of the patch clamp technique. Transfected HEK293 cells were clamped at a holding potential of -60 mV and a steady pulse waveform of 15 s interval was used (activation/deactivation: 40 mV for 2000 ms; recovery: -120 mV for 2 ms; tilting within 2 ms) Rise to 40 mV; deactivated tail current: 40 mV for 50 ms) causing hERG-mediated deactivation of the tail current. During each interpulse interval, the P/n leakage subtraction program records four pulses that are scaled down by a factor of 0.2. The compensation of R _{s is} used until the degree of lack of safety recording damping ringing is allowed.

Compound preparation and application:

Test compounds at different concentrations were applied sequentially to each of the different cells studied. A baseline current of at least 6 scans of steady state is measured prior to administration of the first test compound concentration.

The test compound is dissolved in DMSO to produce a stock mother liquor which is then diluted in DMSO to produce a lower concentration of the desired stock solution. The final dilution in the extracellular buffer was freshly prepared from these stock solutions by a 1:1000 dilution step before each start of the experiment.

data analysis:

The peak current amplitude is measured 3 ms after the ramp rises to +40 mV. For the baseline values and for each concentration, the peak currents for each of the last three scans prior to the administration of the next concentration were averaged. The residual current (I/I ₀ ) of each cell was calculated as the fraction of the actual average peak current and the average baseline peak current. The results are expressed as percent inhibition (%) at 10 μM (1-I/I ₀ )*100%.

In vitro leukemia diagnosis (assay 4)

The phospholipidosis of the test compound was tested using the human hematopoietic U937 cell line. The principle of the test was to analyze the phospholipid content by staining the cells with the fluorescent dye Nile red.

U937 cells were seeded in cell culture plates at 0.5 x 10 ⁶ cells per ml in RPMI medium containing 10% FBS, 1% DMSO, and 0.005% gentamicin. Cells were then incubated with or without different concentrations of test compound for 48 hours under standard culture conditions.

For collection, cells were centrifuged at 130 xg for 4 minutes and washed once with PBS. Next, 2 x 0.5 mL cell suspension was prepared for unfixed cell measurements (0.5 mL for propidium iodide (PI) viability measurements and 0.5 mL for Nile Red measurements).

The remaining cells were fixed with 3.7% formaldehyde for 30 minutes. After a further centrifugation step, the cells were resuspended in 1.3 mL Nile Red treatment solution (1 μg/mL) and incubated for 5 minutes at room temperature.

The cell suspension was then washed twice with 3 mL PBS and centrifuged at 130 xg for 4 minutes. The supernatant was discarded and the cells were resuspended in 0.5 mL PBS and left for flow cytometry.

For Nile red staining of 0.5 mL of unfixed cell samples, 50 μL of spare Nile Red solution (10 μg/mL) was added to each sample. The sample was kept on ice for 5 minutes. Thereafter, it was washed once with 4 mL of PBS (4 ° C, 250 × g for 8 minutes) and finally resuspended in 400 μL of PBS and left for flow cytometry.

For viability measurements, add 12.5 μL of spare PI solution (10 μg/mL) to a 0.5 mL unfixed cell suspension. After incubation for 15 minutes on ice, samples were measured by flow cytometry using a Coulter Epics XL/MCL flow cytometer.

The cell viability of each sample was determined by flow cytometry to measure the PI content of channel 2 (568-590 nm). A cut-off gate for fluorescence-dependent differentiation between living cells and dead cells is defined based on analysis of cell culture control samples. Phosphoplasmosis was analyzed only for samples with >=90% cell viability relative to control samples. To this end, each Nile Red sample (unfixed and fixed sample) was measured by flow cytometry at channel 1 (504-541 nm) and channel 4 (660-680 nm).

For each channel, the relative Nile Red fluorescence intensity of the test sample was calculated and expressed as a percentage of the control fluorescence intensity compared to the control sample. The phospholipidosis test and the first action concentration (FEC) of the test compound are manually performed based on the fluorescence intensity at the wavelengths of the fixed cells and the unfixed cells.

Rat brain A beta reduction test (assay 5)

The in vivo potency of the compounds of the invention was demonstrated in a rat brain A beta reduction (decrease) assay and the data is provided in Table 3. The ability of the compounds of the invention to reduce brain amyloid A[beta] 1-x was demonstrated using a 5 to 6 week old male Sprague-Dawley rat. Compound 1% polysorbate-80 and 0.5% Natrosol ^®, in a single dose as indicated in Table 3 via the oral gavage administered. The animals were sacrificed 3 hours after administration, and the brain was excised, dissected into the cerebellum and the left and right brains, and rapidly frozen in liquid nitrogen. The brain was homogenized in a 20 mM Tris-HCL, pH 8.5, 0.2% Triton-X100 supplemented with a protease inhibitor (cOmplete, Roche Applied Science) at 4 °C using a glass Dune homogenizer. The homogenate was centrifuged at 120,000 x g for 60 minutes at 4 ° C, and the supernatant was collected and Ab1-x was analyzed using a chemoluminescence detection immunoassay (Meso-Scale Discovery, Rockville, MD (MSD)).

Streptavidin 96-well plates (MSD) were pre-blocked with 5% Blocker A solution (MSD) on a cyclotron for 1 hour at room temperature and washed with phosphate buffered saline (PBS) 4 Times. Each well was pre-coated with 20 ng of biotinylated antibody SIG-39155 per well (pure line M3.2, specific for amino acid 10-15 of rodent A beta) and washed with PBS at room temperature for 4 hours. Times. For the Aβ 1-x assay, 25 μl of the purified brain lysate or A β 1-40 standard (8-500 pg/ml, 2× increments) was incubated for 1 hour at room temperature under constant shaking. Each well was washed 4 times with PBS, and 25 μl of detection antibody (MSD-supplied Sulfo-TAG-labeled anti-Aβ40 antibody) was added and incubated at room temperature for 1 hour. After washing 4 times with PBS, 150 μl of Chemiluminescent Detection Reagent (Read Buffer T, MSD) was added and the plate data was read on an MSD Sector Imager 6000 instrument. The calibration curve was fitted to a non-linear four-parameter regression model and the concentration of A[beta] 1-x containing each well of the cleared brain lysate was calculated. The percent Aβ reduction was calculated based on the difference in mean Aβ concentration from the brain of the animals treated with the vehicle alone.

Table 1 shows the following characteristics of the compounds of the present invention: BACE1 inhibitory potency as measured in assay 1, such as the cell inhibition potency measured in assay 2, hERG inhibition as measured in assay 3, and as determined in assay 4 The first action concentration (FEC) of phospholipid disease measured.

Table 2 provides the information displayed in the BACE1 enzyme assay (test 1) A β and cell assay (assay 2) a compound of the present invention, in particular with respect to the particular comparison WO 2010/105179 in the compound has a lower IC ₅₀ inhibition values of significant .

The ability of the compounds of the invention to reduce brain A[beta] was demonstrated in rats as described in assay 5, and its in vivo efficacy data is presented in Table 3.

treatment method

The present invention is directed to a compound suitable for treating a condition or disease having a high beta-type starch deposition or a beta-like starch content in an individual having therapeutic benefit in inhibiting beta-secretase (BACE1) activity, including but not limited to treatment, A disease that ameliorates or prevents a neurodegenerative disorder characterized by cognitive decline, cognitive impairment, dementia, and a disease that produces beta-like starch deposition or neurofibrillary tangles.

The compound of the present invention is suitable for the treatment of Alzheimer's disease, the 21st chromosome trisomy (Down's syndrome), the hereditary cerebral hemorrhage (HCHWA-D) of the Dutch amyloidosis, the senile dementia, the cerebral amygdala Lesions, degenerative dementia, mixed blood vessels and degenerative dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Diffuse Lewy body type of Alzheimer's disease, dry age-related macular degeneration (AMD), and glaucoma. "Dry" AMD is also known as "middle map-like atrophy" caused by atrophy of the retinal pigment epithelial layer beneath the retinal nerve sensory layer, which causes loss of vision by loss of photoreceptors (rods and cones) in the central portion of the eye. . There are currently no medical or surgical treatments for this condition. The treatments available to date (as proposed by the National Eye Institute) include the use of vitamins supplemented with high doses of antioxidants, lutein and zeaxanthin, which slows the progression of dry macular degeneration. Glaucoma increases fluid pressure inside the eye A disease in which nerves cause irreversible damage and cause loss of vision. In experimental glaucoma, Aβ coexists with apoptotic retinal ganglion cells and induces apoptosis in severe retinal ganglion cells in a dose- and time-dependent manner.

Accordingly, the present invention relates to a compound for use as a pharmaceutical or a pharmaceutically acceptable salt thereof.

Furthermore, the invention relates to the use of the compounds for the treatment of diseases and/or conditions which have therapeutic benefit in inhibiting the activity of beta secretase (BACE1).

Furthermore, the invention relates to the use of a compound for the treatment of a neurodegenerative disorder, a condition characterized by cognitive decline, cognitive impairment, dementia and a condition characterized by the production of beta-like starch deposition or neurofibrillary tangles.

Thus, the compounds of the invention are useful in the treatment of Alzheimer's disease, chromosome 21 trisomy (Down's syndrome), Dutch amyloidosis, hereditary cerebral hemorrhage (HCHWA- D), Alzheimer's disease, cerebral amylovascular disease, degenerative dementia, mixed blood vessels and degenerative dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, and degeneration of cortical basal ganglia Disease-related dementia, diffuse Lewy body type Alzheimer's disease, dry AMD and glaucoma.

The invention also provides a method for treating a condition associated with or associated with excessive BACE1 activity in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. The invention also provides a method for inhibiting BACE1 activity in a subject in need thereof, comprising administering to the individual an effective amount of at least one of the disclosed compounds, or a pharmaceutically acceptable salt thereof, and/or a receptor thereof and an effective amount thereof At least one of the disclosed compounds or a pharmaceutically acceptable salt thereof is contacted. The invention also provides a method of improving the deposition of beta-based starch in an individual in need thereof, comprising administering to the individual an effective amount of at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof.

The invention includes for the treatment or amelioration of BACE1-mediated diseases in an individual in need thereof A method of treatment comprising administering to a subject in need thereof an effective amount of a compound of the invention described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

As used herein, the terms "subject" and "patient" are used interchangeably and mean a mammal in need of treatment, such as a companion animal (eg, a dog, a cat, and the like), a domestic animal (eg, a cow, Pigs, horses, sheep, goats and their analogues) and experimental animals (eg rats, mice, guinea pigs and their analogues). Typically, the individual is a human in need of treatment.

As used herein, the term "treating" or "treatment" refers to obtaining the desired pharmacological and/or physiological effect. The effect may be prophylactic (ie, reducing the likelihood of developing a condition or disease) or therapeutic, including partially or substantially achieving one or more of the following: partially or completely reducing the extent of the disease, disorder, or syndrome; improving or improving The clinical symptoms or indications associated with the condition; or the possibility of delaying, inhibiting, or reducing the progression of the disease, condition, or syndrome.

The dose of the compound of the invention which can be administered per day is generally from 0.1 to 3000 mg, preferably from 1 to 2000 mg, more preferably from 10 to 1000 mg, optimally 50 or 500 mg. Each dosage unit preferably contains from 0.1 to 1000 mg, preferably from 25 to 250 mg. The actual pharmaceutically effective amount or therapeutic dose will of course depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any event, the combination will be administered in a dosage and manner that allows for the delivery of a pharmaceutically effective amount based on the patient's unique condition.

Pharmaceutical composition

Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, lozenges, pills, capsules, suppositories, troches, dragees, solutions, syrups, elixirs, sachets, injectables, inhalants and Powder, etc. The content of the pharmaceutically active compound should be in the range of from 0.1 to 95% by weight of the total composition, preferably from 5 to 90% by weight of the total composition.

Suitable lozenges can be obtained, for example, by mixing one or more compounds of the invention with known excipients such as inert diluents, carriers, disintegrating agents, adjuvants, surfactants, binders and/or lubricants. Tablets can also be composed of several layers.

Combination therapy

In one embodiment, the invention encompasses combination therapies for treating or ameliorating the diseases or conditions described herein. Combination therapy comprises administering a combination of at least one compound of the invention and one or more agents selected from the group consisting of gamma-secretase inhibitors or modulators; blocking A beta oligomers or A beta fibrils (eg ELND) -005) a starch aggregation inhibitor such as a formation; a neuroprotective and/or disease modifying substance that acts directly or indirectly; an antioxidant (such as vitamin E or ginkolide); an anti-inflammatory substance (such as a Cox inhibitor; Additionally or exclusively NSAIDs with Aβ-reducing properties; HMG-CoA reductase inhibitors (statin); acetylcholine inhibitors (eg, donepezil, remexemine) Rivastigmine), tacrine, galantamine, tacrine); NMDA receptor antagonists (eg memantine); AMPA receptor agonists; AMPA receptor forward regulation Agents, AMPAkine, monoamine receptor reuptake inhibitors, substances that modulate the condensation or release of neurotransmitters; substances that induce growth hormone secretion (eg, ibutamoren mesylate) Capromorelin; CB-1 receptor antagonist or reverse Antibiotics (such as minocyclin or rifampicin); PDE2, PDE4, PDE5, PDE9, PDE10 inhibitors, GABAA receptor reverse agonists, GABAA receptor antagonists, nicotine A agonist or partial agonist or positive regulator, an α 4 β 2 nicotinic receptor agonist or a partial agonist or positive regulator, an α 7 nicotinic receptor agonist or a partial agonist Agent or positive regulator; histamine H3 antagonist, 5 HT-4 agonist or partial agonist; 5HT-6 antagonist; α2-adrenoreceptor antagonist; calcium antagonist; a muscarinic receptor M1 agonist or a partial agonist or a positive regulator; a muscarinic receptor M2 antagonist; a muscarinic receptor M4 antagonist; a metabotropic glutamate receptor 5 positive regulator; Antidepressants such as citalopram, fluoxetine, paroxetine, seitraline, and trazodone; anti-anxiety agents such as lorazepam And oxazepam; antipsychotics, such as aripiprazole, clozapine, haloperidol, Olanzapine, quetiapine, risperidone, and ziprasidone and to increase the efficacy and/or safety of the compounds of the invention and/or reduce undesirable effects Ways to regulate receptors or other substances in the enzyme. The compounds of the invention may also be used in combination with immunotherapies for the treatment of the above mentioned diseases and conditions (for example, active immunization with A beta or a portion thereof or passive immunization with a humanized anti-A beta antibody or a nanoantibody). Combination therapy comprises co-administering a compound of the invention with one or more other agents, administering the compound and one or more other agents, administering a composition comprising the compound and one or more other agents, or simultaneously administering the compound and one or more Individual compositions of other reagents.

Experimental part

Method of preparing a compound

The compounds of the present invention can be prepared by conventional methods using readily available reagents and starting materials. The reagents used to prepare the compounds of the invention are either commercially available or can be prepared by standard procedures as described in the literature.

The microwave reaction was carried out in a CEM reactor using a discovery SP system.

Where NMR data is provided, the spectra are obtained in Varian-400 (400 MHz) and reported in parts per million lower than the field of tetramethylnonane, together with reference to the deuterated solvent, indicating the number of protons, multiplicity and coupling constant.

The compound was purified by basic preparative HPLC as described below.

method 1:

Mobile phase A: water with 0.05% aqueous ammonia solution; mobile phase B: ACN; flow rate: 25 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex Gemini C18 250*30 mm*5 μm tube Column temperature: 30 ° C 13.7 90 10

Method 2:

Mobile phase A: water with 0.05% aqueous ammonia solution; mobile phase B: ACN; flow rate: 25 mL/min; detection: UV 220 nm/254 nm; column: Durashell C18 250*30 mm*5 μm; tube Column temperature: 30 ° C

LC-MS data were obtained by using the following chromatographic conditions:

HPLC system: Waters ACQUITY; column: Waters ACQUITY CSH ^TM C18 1.7 μM

Guard column: Waters Assy.Frit, 0.2 μM, 2.1 mm; column temperature: 40 °C

Mobile phase: A: TFA: water (1:1000, v: v) mobile phase B: TFA: ACN (1:1000, v: v); flow rate: 0.65 mL/min; injection volume: 2 μL; acquisition time : About 1.5 min.

Mass spectrometer parameters

Mass spectrometer: Waters SQD; ionization: positive ion electrospray ionization (ESI); mode scan (100-1400 m/z every 0.2 seconds); ES capillary voltage: 3.5 kv; ES cone voltage: 25 v source temperature: 120 °C; Dissolution temperature: 500 ° C; Desolvent gas flow: Nitrogen setting 650 (L / h); Cone gas flow: Nitrogen setting 50 (L / h)

For Example 10 , Step 2, and Alternative Synthesis of Intermediate 38 , Steps 1 and 2, the following chromatographic conditions and instruments were used:

LC-MS data were obtained by using the following chromatographic conditions:

HPLC system: Agilent 1100 Series

String: Zorax Eclipse XDB-C8, 2.1 × 50 mm

Column temperature: 35 ° C

Mobile phase: A: Formic acid: water (1:1000, v:v)

B: Formic acid: ACN (1:1000, v:v)

Flow rate: 0.60 mL/min

Injection volume: 2 μL

Residence time: about 1-4 min

Get time: about 5 min

Mass spectrometer parameters

Mass Spectrometer Parameters: Agilent 77

Ionization positive ion electrospray ionization (ESI)

Mode scan (100-800 m/z every 0.2 seconds)

ES capillary voltage: 3.5 kv

ES cone voltage: 25 v

Source temperature 120 ° C

Dissolution temperature: 500 ° C

Desolvent gas flow: Nitrogen setting 650 (L/h)

Cone gas flow: nitrogen setting 50 (L/h)

For Example 27 , the following chromatographic conditions and instruments were used:

HPLC System: Waters Alliance/DA-und MS-Detector

Column: Waters XBridge C18, 4.6×30 mm, 3.5 μm

The SFC separation and characterization of the compounds was carried out using the following method.

Method A:

Instrument: Thar SFC 80; column: AD 250mm*30mm, 5 μm; mobile phase: A: supercritical CO ₂ , B: IPA (0.05% DEA), 60 ml/min A: B = 80:20; tube Column temperature: 38 ° C; nozzle pressure: 100 bar; nozzle temperature: 60 ° C; evaporator temperature: 20 ° C; micro-regulator temperature: 25 ° C; wavelength: 220 nm.

Method B:

Instrument: SFC MG2; column: OJ 250mm*30mm, 5 μm; mobile phase: A: supercritical CO ₂ , B: MeOH (0.05% DEA), 70 ml/min A: B = 90:10; column temperature : 38 ° C; nozzle pressure: 100 bar nozzle temperature: 60 ° C; evaporator temperature: 20 ° C; micro-regulator temperature: 25 ° C; wavelength: 220 nm

The following techniques, solvents and reagents can be mentioned by their abbreviations:

Example 1

Step 1: Synthesis of intermediates 3

Premix the mixture of compound 1 (50.0 g, 236 mmol) and methyl acrylate (42.0 g, 472 mmol) in dry THF (900 mL) at 0 ° C and add t -BuOK (31.8 g, 284 mmol, 1.1 eq.), then the mixture was warmed to room temperature over 1 hour and stirred at room temperature for 40 min. DMF (200 mL) and EtOAc (74 g, 472 mmol). The THF was removed under reduced pressure. The residue was diluted with H ₂ O (300 mL) and extracted with EtOAc, and concentrated to obtain a crude compound 2 (120.0 g). This product was used as it is in the next step.

A mixture of compound 2 (120.0 g, 310 mmol) and LiCl (130.0 g, 3100 mmol) in DMSO (900 mL) was refluxed overnight. The mixture was quenched with water (3L) andEtOAcEtOAc The separated organic phase was dried and concentrated under reduced pressure. By silica gel column chromatography (petroleum ether: EtOAc = 20: 1) The residue was purified to give intermediate 3 (15 g, 20%) .

¹ H NMR: (CDCl ₃ ): δ 7.91 (s, 1H), 7.74 (dd, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 3.80 (s, 2H), 2.48- 2.53 (m, 2H), 2.33-2.49 (m, 1H), 2.15-2.23 (m, 1H), 1.75-1.95 (m, 4H), 1.21-1.40 (m, 1H), 0.88 (t, J = 8.0) Hz, 3H).

Step 2: Synthesis of intermediates 5

Intermediate 3 (6.0 g, 18.7 mmol), NaBH ₄ (355 mg, 9.3 mmol) and CeCl ₃ .7H ₂ O (70) were added to a mixture of THF (20 mL) and MeOH (5 mL). Mg, 0.19 mmol). The mixture was stirred at -78 ℃ 20 minutes, saturated NH ₄ Cl solution (30 mL) suspension, and (400 mL × 4) extracted with EtOAc. EtOAc phases were combined and concentrated to give crude compound 4 (6.5 g, crude compound). MeI (11.4 g, 80.0 mmol) was added to a mixture of compound 4 (6.5 g, 20.0 mmol) and NaH (3.2 g, 80.0 mmol) in DMF (100 mL). The mixture was stirred overnight at room temperature. H ₂ O mixture was suspended, extracted with EtOAc, concentrated to give crude product, which by silica gel column (eluent: petroleum ether: ethyl acetate 20: 1 to 15: 1) to afford intermediate 5 (3.5 g, 56%).

_{LC-MS: t R = 1.315} min, MS (ESI) m / z 339.1 [M + H] +.

¹ H NMR: (CDCl ₃ ): δ 7.88 (s, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.39 (s, 3H), 2.97(s,2H),2.88-2.94(m,1H),2.21-2.26(m,1H),1.81-1.87(m,1H),1.70-1.78(m,1H),1.40-1.59(m,4H) ), 1.12-1.39 (m, 2H), 0.88 (t, J = 8.0 Hz, 3H).

Step 3: Synthesis of intermediates 6A and 6B

A mixture of Intermediate 5 (3.5 g, 10.4 mmol) and EtOAc (EtOAc) (EtOAc) ( S ) -N - T -butylsulfinamide (1.6 g, 11.6 mmol) was added and the resulting mixture was stirred at 80 ° C overnight under N ₂ atmosphere. The reaction mixture was then cooled and water (400 mL) was added and filtered. The aqueous layer was extracted with EtOAc (3×400 mL). The separated organic phases were combined and dried and concentrated. By silica gel column chromatography (petroleum ether: EtOAc = 20: 1) and the residue was purified using the following elution order obtained intermediate compound 6A (1.5 g, 33%) and 6B (1.5 g, 33%) .

Step 4: Synthesis of intermediate 7B

At -78 deg.] C, under N ₂ atmosphere, to ethoxy - ethylene (1.3 g, 17.0mmol) in dry mixture (20 mL) in of THF was added dropwise t -BuLi (13.0 mL, 17.0 mmol , hexyl 1.3 M in the alkane and stirred for 20 minutes. The resulting mixture was then stirred at 0 ° C for an additional 45 minutes. Intermediate 6B (1.5 g, 3.4 mmol) in dry THF (20 mL) was then evaporated. The reaction was discontinued and the (3 × 300 mL) and extracted with EtOAc with saturated NH ₄ Cl (50 mL). The organic phases were combined and concentrated to obtain a residue, and by silica gel column (petroleum ether: EtOAc = 20: 1) to afford Intermediate 7B (1.2 g, 69%) .

Step 5: Synthesis of Intermediate 8B

Intermediate 7B (1.2 g, 2.4 mmol) was added to DCM:MeOH (5:1, 20 mL) and the mixture was chilled to -78 &lt;0&gt;C and the mixture was bubbled through the mixture for 20 min. The mixture was then purified to N ₂ and Me ₂ S in the processing at -78 ℃. The reaction was then allowed to warm to rt and stirred for 3 h. The solvent was removed in vacuo and purified title title mjjjjjjjjj

_{LC-MS: t R = 1.351} min, MS (ESI) m / z 516.1 [M + H +].

Step 6: Synthesis of Intermediate 9B

Add 4 M HCl to MeOH (10 mL) containing compound 8B (860 mg, 1.7 mmol) Solution (2 mL). The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give crude compound 9B (800 mg). The residue was used in the next step without further purification.

Step 7: Synthesis of intermediate 10B

Intermediate 9B (500 mg, 1.9 mmol), Zn(CN) ₂ (300 mg, 2.6 mmol), Pd ₂ (dba) ₃ (150 mg, 0.16 mmol) in a CEM microwave reactor at 120 °C , dppf (160 mg, 0.32 mmol) and a suspension of Zn powder (60 mg, 0.9 mmol) in DMF (15 mL) for 3 h. The mixture was concentrated in vacuo, and by silica gel column (eluent: petroleum ether: EtOAc 20: 1 to 8: 1) to give the residue to give compound 10B (150 mg, 40%) .

Step 8: Synthesis of intermediate 11B

Intermediate 10B (150 mg, 0.42 mmol) was added to DCM (10 mL), H ₂ O (10 mL) and NaHCO ₃ (350 mg, 4.2 mmol). To this mixture was added thiophosgene (100 mg, 0.84 mmol), and stirred at room temperature for 50 min and extracted with DCM (3×40 mL). The organic layer was washed with brine (2 × 40 mL), dried and the solvent was removed under reduced pressure to obtain a crude compound 11B (150 g, 93%) , which was used without further purification in the next step.

Step 9: Synthesis of intermediate 12B

2-Aminomethylpyrimidine (67 mg, 0.78 mmol) and TEA (395 mg, 3.90 mmol) were added to a mixture of compound 11B (150 mg, 0.39 mmol) in THF (5 mL). The mixture was stirred overnight at room temperature. The reaction was diluted with water and extracted with EtOAc EtOAc. By column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the residue to give 12B (100 mg, 70%) .

_{LC-MS: t R = 1.204} min MS (ESI) m / z 462.2 [M + H] +.

Step 1: Synthesis Example 1

Add MeOH containing compound 12B (100 mg, 0.22 mmol) of (10 mL) and NH ₄ OH (3 mL), followed by _{t-BuO 2 H (1 mL} ). After the addition, the mixture was stirred at room temperature for 24 hours. The mixture was quenched with a saturated solution of Na ₂ S ₂ O ₃ (0.5 mL). The residue was partitioned between EtOAc and _{H 2 O (10 mL) (} 20 mL). The organic layer was separated and washed with brine (10 mL The residue was purified by HPLC (Method 1) to give Compound Example 1 (14.60 mg, 15%).

_{LC-MS: t R = 0.933} min, MS (ESI) m / z 445.2 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 8.74 (d, J = 5.2 Hz, 2H), 7.61 (dd, J = 7.6, 1.6 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 5.2 Hz, 1H), 4.94 (s, 2H), 3.38 (s, 3H), 3.17 (s, 2H), 2.80-2.87 (m, 1H), 2.08- 2.13 (m, 1H), 1.90- 1.94 (m, 1H), 1.38-1.85 (m, 2H), 1.22-1.39 (m, 3H), 1.12-1.18 (m, 2H), 0.76 (t, J = 8.0) Hz, 3H).

Example 2

This compound was synthesized from Intermediate 10B of Example 1 as shown in the scheme below.

Step 1: Synthesis of intermediates 13

Sodium hydride (29.9 g, 755 mmol, 60% in mineral oil) was added to a stirred solution of thiourea (23 g, 302 mmol) in THF (5.0 L) at EtOAc. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 10 min. The mixture was again cooled to 0 ° C, ditributyl dicarbonate (138 g, 635 mmol) was added and the ice bath was removed after stirring for 30 min. The resulting slurry was stirred for a further 2 hours at room temperature. Subsequently, the reaction was suspended in saturated aqueous NaHCO ₃ (500 mL). The reaction mixture was poured into water (5 mL) The combined organic layers were dried, filtered and concentrated in vacuo to give 13 (80 g, 96%) of a white solid intermediate, which was used without further purification in the next step.

NaH (60% in mineral oil, 720 mg, 18.0 mmol) was added to a mixture of intermediate 13 (4.14 g, 15.0 mmol) and dry THF (300 mL). The reaction mixture was stirred at 0&lt;0&gt;C for 1 h then EtOAc (3. <RTI ID=0.0></RTI></RTI><RTIgt; Next, a solution of 4 (aminomethyl) tetrahydropyran (2.5 g, 16.5 mmol) and _{Et 3 N (3.03 g / 4.16} mL, 30.0 mmol) in dry of THF (130 mL) and the resulting reaction product in a chamber Stir under temperature overnight. Add H ₂ O (150 mL) and the mixture (3 × 200 mL) to quench the reaction and extracted with EtOAc. The combined organic layers were dried and the solvent was removed under reduced pressure. Purification by flash column chromatography of the residue, obtained as a white solid of compound 13 (3.54 g, 86%) .

_{LCMS: t R = 0.973 min;} MS (ESI) m / z 219 [Mt-Bu] +.

Step 2: Synthesis of intermediates 14

Compound 13 (2.3 g, 8.4 mmol), EDCI (2.5 g, 14.0 mmol) and DIEA (1.7 g, 14.0 mmol) were added to a mixture of compound 10B (2.5 g, 7.0 mmol) in 30 mL DMF. The mixture was stirred overnight at room temperature. It was extracted with EtOAc (3×40 mL)EtOAcEtOAcEtOAc By column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the residue to give 14 (2.7 g, 75%) .

_{LC-MS: t R = 0.972} min, MS (ESI) m / z 495.3 [Mt-Bu] +.

Step 3: Synthesis Example 2

To a mixture of intermediate 14 (2.7 g, 4.9 mmol) in DCM (30 mL) After the addition, the mixture was stirred at room temperature for 1 hour. By NaHCO ₃ solution and the reaction mixture was adjusted to pH 8.0-9.0. The organic layer was concentrated under reduced pressure. By column chromatography (petroleum ether: ethyl acetate = 1: 1) to give the residue to obtain a white solid compound of Example 2 (1.83 g, 83%) .

_{LC-MS: t R = 0.897} min, MS (ESI) m / z 451.2 [M + H] +.

¹ H-NMR: (CD ₃ OD): δ 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.33 (s, 1H), 3.92-3.98 (m) , 2H), 3.37-3.43 (m, 7H), 3.20 (m, 2H), 2.78-2.83 (m, 1H), 2.16-2.20 (m, 1H), 1.87-2.03 (m, 1H), 1.71-1.77 (m, 1H), 1.58-1.62 (m, 1H), 1.51-1.54 (m, 2H), 1.28-1.37 (m, 7H), 1.09-1.10 (m, 1H), 0.76 (t, J = 7.6 Hz , 3H).

Example 3

Synthetic intermediate 18

Step 1: Synthesis of intermediates 16

At -30 deg.] C, under a nitrogen atmosphere, was added to a solution of methylmagnesium bromide (14 mL, 42 mmol, Et 2 O in 3.0 M) of compound 15 (2.0 g, 10.6 mmol) in dry THF (20 mL) a mixture of them. The mixture was stirred at -30 °C for 4 hours, then quenched by the addition of water (40 mL) and aqueous HCl (50 mL, 1 M) with stirring. The mixture was separated and the aqueous extracted with EtOAc EtOAc Combined organic layers were washed with brine (2 × 50 mL), dried, filtered and concentrated in vacuo to give a colorless oil of crude Intermediate 16 (2.1 g, 100% crude), which was used without further purification directly In the next step.

¹ H NMR: (CDCl ₃ ): δ 4.97 (br, 1H), 3.10 (s, 2H), 2.17 (br, 1H), 1.44 (s, 9H), 1.20 (s, 6H).

Step 2: Synthesis of intermediates 17

DAST (2.3 mL, 17.4 mmol) was added to a mixture of intermediate 16 (3.0 g, 15.9 mmol, EtOAc) The mixture was stirred at -78 °C for 1 hour and warmed to room temperature overnight. The mixture was then cooled to 0 ° C and quenched by slowly adding a saturated aqueous layer of NaHCO ₃ (30 mL) with stirring at 0 °. The mixture was separated and the aqueous extracted with DCM (2×20 mL). Combined organic layers were washed with brine (2 × 30 mL), dried, filtered and concentrated in vacuo to give the crude Intermediate 17 (2.5 g, 76% crude), which was used without further purification was used directly in the next step.

¹ H NMR: (CDCl ₃ ): δ 4.82 (br, 1H), 3.30 - 3.35 (d, J = 6.0 Hz, 1H), 3.24 - 3.26 (d, J = 6.0 Hz, 1H), 1.44 (s, 9H) , 1.37 (s, 3H), 1.35 (s, 3H).

¹⁹ F NMR: (CDCl ₃ 400 MHz): δ - 144.93.

Step 3: Synthesis of intermediates 18

Add HCl-II to a mixture of intermediate 17 (2.0 g, 10.5 mmol, crude) in dry DCM (10 mL) Mixture (10 mL, 40 mmol, two 4 of the M). The mixture was stirred at room temperature for 2 hours, after which time the solvent was concentrated in vacuo. The residue in DCM: petroleum ether mixtures: washed (3 × 10 mL) (1 1), and the precipitate was collected and dried in vacuo to give crude compound 18 (1.1 g), which was used directly without purification in the next step .

¹ H NMR: (CD ₃ OD): δ 3.15 - 3.25 (d, J = 20.0 Hz, 2H), 1.51 (s, 3H), 1.48 (s, 3H).

¹⁹ F NMR: (CDCl ₃ 400 MHz): δ-147.59.

Example 3

The procedure of Example 1 was prepared following the same procedure of Example 1 and using the procedure of intermediate 9 18, intermediate from Example 11B Example 1 of Synthesis Example 3.

_{LC-MS: t R = 1.12} min, MS (ESI) m / z 427 [M + H] +.

¹ H-NMR: (CD ₃ OD) δ 7.65 (dd, 1H, J = 8, 2 Hz), 7.51 (d, 1H, J = 8 Hz), 7.31 (s, 1H), 3.72 (dd, 2H, J=22,4 Hz), 3.37 (s, 3H), 3.20 (ap q, 2H, J=16 Hz), 2.82 (m, 1H), 2.18 (m, 1H), 1.90 (m, 1H), 1.79 -1.70 (m, 1H), 1.52-11.22 (m, 10H), 1.21-1.09 (m, 1H), 0.77 (t, 3H, J = 7 Hz).

Example 4

Synthetic intermediate 25

Step 1: Synthesis of intermediates 20

Stir a mixture of dihydro-2H-piperidin-4(3H)-one ( 19 , 50.0 g, 500 mmol) and 2-chloroacetonitrile (35.0 g, 350 mmol) in tert-butanol (50 mL) for 30 min . A solution of t- BuOK (60 g, 550 mmol) in tert-butanol (500 mL) was added to this mixture over 40 min. The reaction mixture was stirred at room temperature for 16 hours. It was diluted with water and stopped with 10% HCl. The reaction mixture was concentrated to 1/3 of its original volume and extracted four times with diethyl ether. Combined organic layers were washed with brine, dried over MgSO ₄ dried, filtered, and concentrated to give intermediate 20 (57 g), which was used directly without purification in the next step.

Step 2: Synthesis of intermediates 21

Intermediate 20 (57 g) and dichloromethane (200 mL) were mixed in a polypropylene bottle. The vial was cooled to 0 °C and 70% hydrogen fluoride-pyridine (50 mL) was slowly added. The mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (500 mL) and poured into a saturated aqueous solution of NaHCO _3. Additional solid NaHCO ₃ was carefully neutralized mixture until bubbling ceased. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×500 mL). Combined organic layers were at 1% HCl solution, washed with brine, dried (MgSO _4), filtered, and concentrated to give Intermediate 21 (54 g), which was used directly without purification in the next step.

¹ H NMR: (CDCl ₃ ): δ 4.37 (m, 2H), 3.96 - 2.70 (m, 4H), 1.97-1.81 (m, 4H).

Step 3: Synthesis of intermediates 22

Sodium borohydride (20 g, 509 mmol) was added to a mixture of intermediate 21 (54 g; 340 mmol) in 2-propanol (1000 mL) and water (250 mL). The mixture was stirred and allowed to warm to room temperature over 3 hours. The reaction was quenched with acetone and stirred for an additional 1 hour. The clear liquid and solid were separated by decantation. The solid was washed with additional EtOAc and decanted. The combined organic solution was concentrated. Flash column chromatography using silica gel (5-20% EtOAc in hexanes containing the eluted) to afford the residue, to obtain a liquid form of intermediate 22 (22 g, 3 steps 40%).

¹ H NMR: (CDCl ₃ ): δ: 3.82-3.77 (m, 4H), 3.72-3.52 (dd, J = 20.8, 6.4 Hz, 2H), 2.69 (s, 1H), 1.82-1.60 (m, 4H) .

Step 4: Synthesis of intermediates 23

MsCl (25.8 g, 225 mmol) was added to a mixture of intermediate 22 (20 g, 150 mmol) and triethylamine (22.7 g, 225 mmol) in DCM (200 mL). The mixture was stirred at room temperature for 2 hours, followed by the addition of water. The aqueous layer was extracted with DCM (2×200 mL). The solvent was dehydrated and removed to give a crude intermediate 23 (30 g, 100%) which was used in the next step without further purification.

¹ H NMR: (CDCl ₃ ): δ: 4.22 (d, J = 20.0 Hz, 2H), 3.87-3.82 (m, 4H), 3.06 (s, 3H), 1.88-1.68 (m, 4H).

Step 5: Synthesis of intermediates 24

At 120 ℃, 23 (10 g, 47 mmol) was added to a mixture of intermediate and DMF (150 mL) of the _{NaN 3 (16 g, 250 mmol} ) and _{NaHCO 3 (9.3 mg, 100 mmol} ). The mixture was stirred at 120 &lt;0&gt;C for 20 h. The solvent was removed in vacuo and dehydrated to obtain a crude intermediate 24 (8 g), which is used without further purification in the next step.

Step 6: Synthesis of intermediates 25

Pd/C (0.8 g, 10% content) was added to a mixture of intermediate 24 (8 g, 50 mmol) in ethyl acetate (100 mL), and the mixture was degassed and exchanged with hydrogen. Times. The final mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 24 hours. The catalyst was filtered through Celite ^® and the pad (2 × 50 mL) washed with EtOAc. The combined filtrate was concentrated under reduced pressure to give Intermediate 25 (5.3 g, 80%). _{^{1 H NMR: (CD 3 OD}} ): δ 3.83-3.79 (m, 4H), 2.76-2.71 (d, J = 8.0 Hz, 2H), 1.83-1.65 (m, 4H).

¹⁹ F NMR: (CD ₃ OD, 400 MHz) δ: -169.66.

Example 4

Example 4 was synthesized from Intermediate 11B using Intermediate 25 instead of 2-pyrimidinylmethylamine in the same procedure as described in Example 1 .

_{LC-MS: t R = 0.98} min, MS (ESI) m / z 469 [M + H] +.

¹ H-NMR: (CD ₃ OD) δ 7.64 (d, 1H, J = 8 Hz), 7.50 (d, 1H, J = 8 Hz), 7.31 (s, 1H), 3.84 - 3.65 (m, 6H) , 3.36 (s, 3H), 3.19 (ap q, 2H, J = 16 Hz), 2.81 (m, 1H), 2.17 (m, 1H), 1.89-1.66 (m, 6H), 1.50-1.37 (m, 3H), 1.34 (m, 2H), 1.20-1.11 (m, 1H), 0.76 (t, 3H, J = 8 Hz).

Example 5

Step 4: Synthesis of intermediate 7A

At -78 deg.] C, under N ₂ atmosphere to ethoxyethylene (1.3 g, 17.0 mmol) in a mixture of anhydrous (20 mL) in of THF was added dropwise t -BuLi (13.0 mL, 17.0 mmol , hexane 1.3 M) and the mixture was stirred for 20 minutes. The resulting mixture was stirred at 0&lt;0&gt;C for additional 45 min and EtOAc (EtOAc &lt;RTIgt; The reaction was discontinued and the (3 × 300 mL) and extracted with EtOAc with saturated NH ₄ Cl (50 mL). The organic phases were combined and concentrated to give a crude material. It was purified by a hydrazine cartridge (petroleum ether: EtOAc = 20:1) to afford compound 7A (1.2 g, 69%).

Step 5: Synthesis of Intermediate 8A

A mixture of compound 7A (1.2 g, 2.4 mmol) in DCM: MeOH = 5:1 (20 mL). Mixture was purged to N ₂ and with Me ₂ S (5 mL) treated at -78 ℃, then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed in vacuo and purified title title mjjjjjjjj _{LC-MS: t R = 1.333} min; MS (ESI) m / z 516.1 [M + H] +.

Step 6: Synthesis of Intermediate 9A

Add 4 M HCl to a mixture of compound 8A (860 mg, 1.7 mmol) in MeOH (10 mL) Solution (2 mL). The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to give EtOAc (EtOAc): _{LC-MS: t R = 0.976} min; MS (ESI) m / z 361.1 [M + H] +.

Step 7: Synthesis of intermediate 10A

Compound 9A (500 mg, 1.9 mmol), Zn(CN) ₂ (300 mg, 2.6 mmol), Pd ₂ (dba) ₃ (150 mg, 0.16 mmol), dppf (160 mg, 0.32 mmol) and Zn powder ( A mixture of 60 mg, 0.9 mmol) in DMF (15 mL) was heated to 120 ° C for 3 h in a CEM microwave reactor. The mixture was concentrated in vacuo and the by silica gel column (eluent: petroleum ether: EtOAc 20: 1 to 8: 1) to give the residue to give compound 10A (300 mg, 40%) . _{LC-MS: t R = 0.880} ; MS (ESI) m / z 308.1 [M + H] +.

Step 8: Synthesis of intermediate 11A

To a solution of 10A (300 mg, 0.84 mmol) of _{DCM (10 mL), H 2} O (10 mL) and _{NaHCO 3 (655 mg, 8.4 mmol} ) in the mixture was added thiophosgene (180 mg, 1.68 mmol). The mixture was stirred for 50 minutes, followed by (3 × 40 mL) and extracted with with DCM, brine (2 × 40 mL), dried and the solvent was removed under reduced pressure to obtain a crude compound 11A (300 g), which was used without further purification by In the next step.

Step 9: Synthesis of intermediate 12A

To a solution of Compound 11A (200 mg, 0.50 mmol) THF (10 mL), R- (2-aminomethyl)tetrahydrofuran (61 mg, 0.6 mmol) and triethylamine (2 mL, 5.0 mmol). The mixture was stirred overnight at room temperature. The reaction was diluted with water and extracted with EtOAc EtOAc. By column chromatography (petroleum ether: EtOAc = 10: 1) The residue was purified to give 12A (180 mg, 79%) .

Step 10: Synthesis Example 5

And NH ₄ OH (3 mL) was added a mixture of t -BuO ₂ H solution of intermediate 12A (250 mg, 0.54 mmol) in MeOH (10 mL) (1 mL , 9M hexanes) and stirred at room temperature for 24 hour. The reaction was quenched by saturated Na ₂ S ₂ O ₃ (0.5 mL). The residue was partitioned between EtOAc and _{H 2 O (10 mL) (} 20 mL). The organic layer was separated and washed with brine (10 mL The residue was purified by HPLC (Method 1) to afford Example 5 (89.10 mg, 52%).

LC-MS: </RTI>^< RTI ID=0.0>^</RTI>

¹ H NMR: (CD ₃ OD): δ 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 4.08-4.01 (m, 1H), 3.63-3.90 (m, 4H), 3.33 (s, 3H), 3.09-3.20 (m, 2H), 2.74-2.79 (m, 1H), 1.80-2.06 (m, 5H), 1.65-1.78 ( m,1H), 1.55-1.64 (m, 2H), 1.29-1.35 (m, 3H), 1.07-1.29 (m, 1H), 0.89-0.96 (m, 1H), 0.85 (t, J = 7.6 Hz, 3H).

Example 6

Step 1: Synthesis of intermediates 27

The dried 3 L flask was charged with 6-bromo-1-indanone (100 g, 473.8 mmol), methyl acrylate (86.4 g, 90 mL, 995 mmol, 2.1 eq.) and anhydrous THF (800 mL). The flask was immersed in an ice water cooling bath and stirred. Initially, tBuOK (0.5 g) was carefully added and after 2 minutes a second tBuOK (0.5 g) was added. The cooling bath was removed and the remaining tBuOK (63 g) was added portionwise over 20 min (total 64 g, 568.6 mmol, 1.2 eq.). The mixture was stirred for a further 2 hours at room temperature. DMF (240 mL) was added to EtOAc EtOAc (EtOAc)EtOAc. The reaction was stopped with a 10% citric acid solution. Next, the reaction mixture was concentrated under reduced pressure to remove most solvent and then filtered. The filter cake was washed with water then MeOH afforded crude intermediate 26 (200 g).

Was added _LiOH-2 O to 26 (200 g, 547.6 mmol, crude compound) compound in THF / H (1.8 L / 1.8 L) in a solution of the ₂ O (92 g, 2190 mmol, 4.0 equiv). The mixture was stirred at room temperature for 16 hours and then at 70 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF and filtered. The filter cake was washed with H ₂ O, followed by stirring with MeOH (50 mL) with a few minutes and filtered again, and with an additional amount of MeOH (50 mL) and washed. The solid was collected to give intermediate 27 (75 g, 51.7%).

Step 2: Synthesis of intermediates 29

A three-necked flask was charged with CeCl ₃ .7H ₂ O (1.2 g, 3.3 mmol) and anhydrous MeOH (60 mL) under a nitrogen atmosphere, and stirred to give a clear solution. Compound 27 (10.0 g, 32.6 mmol) and anhydrous THF (240 mL) were added and the mixture was cooled to -78. NaBH ₄ (0.4 g, 13.0 mmol) was added under vigorous nitrogen with stirring at -78 °C. The mixture was stirred at -78 °C for 20 minutes. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH ₄ Cl (100 mL) and H ₂ O (200 mL) with stirring at -78 °C. The mixture was allowed to slowly warm to ambient temperature. The mixture was extracted with EtOAc (3×150 mL). Combined organic layers were in _{H 2 O (2 × 200 mL} ), brine (2 × 200 mL), dried, filtered and concentrated in vacuo by silica gel column chromatography (petroleum ether: EtOAc (20: 1 to The residue was purified by 3:1) elution to afford intermediate 28 (7.5 g, 75%). _{LC-Ms: t R = 3.195} min: MS (ESI) m / z 311.0 [M + H +].

¹ H NMR: (CDCl ₃ ): δ 7.59 (s, 1H), 7.22-7.25 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 6.88-6.91 (dd, J = 2.4, 8.4 Hz , 1H), 6.80-6.81 (d, J = 2.4 Hz, 1H), 5.84 (s, 1H), 4.87 (s, 2H), 4.31-4.36 (m, 2H), 3.50-3.55 (q, J = 6.8 Hz, 2H), 3.15-3.25 (m, 1H), 3.09-3.14 (d, J = 15.6 Hz, 1H), 3.00-3.06 (d, J = 15.2 Hz, 1H), 1.90-2.10 (m, 3H) , 1.25-1.50 (m, 5H), 1.15 - 1.25 (t, J = 6.4 Hz, 3H).

NaH (60% in mineral oil, 0.96 g, 40 mmol) was added to a mixture of compound 28 (6.18 g, 20 mmol) in DMF (20 mL). Then, the mixture was stirred at 0 °C for 2 hours, then MeI (3.5 mL) was added to the mixture and stirred overnight. And mixtures of H ₂ O (40 mL) was diluted with EtOAc (40 mL), in EtOAc (2 × 60 mL) and extracted. The combined organic phases were dried and the solvent was removed to afford Intermediate 29 (5.0 g).

Step 2: Synthesis of intermediates 30A and 30B

Ti(OEt) ₄ (35.0 g, 153 mmol) was added to a solution of Intermediate 29 (5.0 g, 15.3 mmol) in THF (100 mL). After stirring at room temperature for 1 hour, ( S ) -N -tert-butylsulfonamide (7.4 g, 61.2 mmol) was added. The reaction mixture was stirred at reflux overnight and the mixture was partitioned between H ₂ O (80 mL) and EtOAc (80 mL) at. The mixture was filtered and the filtrate was extracted with EtOAc EtOAc. The combined organic layers were washed with brine (50 mL By using the following order of elution chromatography on silica gel column (petroleum ether: EtOAc = 20: 1) The residue was purified to give Intermediate 30A (1.6 g, 35%) and 30B (1.4 g, 33%) .

Synthesis Example 6

Intermediate 30A was further processed as described in steps 4 through 10 of Example 5. In step 9, 2-aminomethylpyrimidine is used in place of R- (2-aminomethyl)tetrahydrofuran.

</RTI>^< RTI ID=0.0>^</RTI>^< RTI ID=0.0>^</RTI>

¹ H NMR: (CD ₃ OD): δ 8.78 (d, J = 4.8 Hz, 2H), 7.76 (s, 1H), 7.75 (dd, J = 6.0, 1.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H) 7.44 (t, J = 5.2 Hz1H), 5.16 (m, 2H), 3.38 (s, 3H), 3.24 (m, 2H), 2.79 (m, 1H), 2.15 (m, 1H), 1.74 (m, 1H), 1.65 (d, J = 6.8 Hz, 1H), 1.39-1.57 (m, 4H), 0.99 (d, J = 6.4 Hz, 3H).

Example 7

It was synthesized by a procedure similar to that described in Example 6 . Intermediate 30A was further processed as described in steps 4 through 10 of Example 1. Example 7 was obtained by using (2-methoxy)ethylamine in Step 9 followed by oxidation as described in Step 10.

LC-MS: tR = 1.08 min , MS (ESI) m / z 397 [M + H] +.

¹ H NMR: (CD ₃ OD) δ 7.74 (d, 1H, J = 8 Hz), 7.63 (d, 1H, J = 1 Hz), 7.57 (d, 1H, J = 8 Hz), 4.02-3.95 ( m,1H), 3.89-3.83 (m, 1H), 3.54 (m, 2H), 3.36 (s, 3H), 3.35 (s, 3H), 3.24 (ap q, 2H, J = 16 Hz)), 2.75 (m, 1H), 2.10 (m, 1H), 1.79 (dt, 1H, J = 13, 2 Hz), 1.56 (m, 1H), 1.41 (m, 3H), 1.14 (t, 1H, J = 13 Hz), 1.01 (d, 3H, J = 6 Hz).

Example 8

It was synthesized by a procedure similar to that described in Example 6 . As in Example 1, Step 9 using the (3-methyl-oxetan-3-yl) methanamine, followed by the oxidation as described in Step 10, to give Example 8.

LC-MS: </RTI>^< RTI ID=0.0>^</RTI>

¹ H NMR: (CD ₃ OD): δ 7.66-7.64 (d, J = 7.2 Hz, 1H), 7.51-7.49 (d, J = 7.6 Hz, 1H), 7.34 (s, 1H), 4.72-4.67 ( m, 2H), 4.29-4.25 (m, 2H), 3.74-3.59 (m, 2H), 3.37 (s, 3H), 3.25-3.14 (m, 2H), 2.74-2.67 (m, 1H), 2.08- 2.03 (m, 1H), 1.80-1.53 (m, 3H), 1.30 (m, 5H), 1.08 (m, 1H), 0.90 (m, 3H).

Example 9

It was synthesized by a procedure similar to that described in Example 6 . As in Example 1, Step 9, the embodiment using 4- (aminomethyl) pyridine, followed by oxidation to the embodiment as described in Example 6, Step 10, obtained in Example 9.

_{LCMS: t R = 0.88 min,} MS (ESI) m / z 431.2 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 9.05 (s, 1H), 8.70-8.71 (d, J = 5.2 Hz, 1H), 7.60-7.62 (d, J = 7.6 Hz, 1H), 7.44-7.47 ( m,3H), 4.86 (s, 2H), 3.35 (s, 3H), 3.10-3.20 (q, 2H), 2.70-2.71 (m, 1H), 2.04-2.06 (m, 1H), 1.70 (m, 2H), 1.491 (m, 1H), 1.30-1.33 (m, 2H), 1.15-1.18 (m, 1H), 0.95-0.96 (d, J = 6.0 Hz, 3H).

Example 10

Step 1: Synthesis of intermediates 32

Add t-BuOK (58.5 g, 521.2 mmol, 1.1 eq.) to a mixture of 6-bromo-indol-1-one (100.00 g, 473.8 mmol) in anhydrous THF (1 L). Thereafter, the mixture was allowed to warm to room temperature and stirred for additional 10 minutes, then methyl methacrylate (49.8 g, 53.2 mL, 497.5 mmol, 1.05 eq.) was added in one portion. After 2 hours, methyl acrylate (49.0 g, 51.2 mL, 568.6 mmol, 1.2 eq.) was added to the mixture. After 3 hours at room temperature, MeI (101 g, 44.3 mL, 710.7 mmol, 1.5 eq.) was added to the mixture and stirred for 16 hr. H ₂ O (1 L) was added followed by LiOH*H ₂ O (79.5 g, 1895.2 mmol, 4.0 eq.), and the mixture was stirred at room temperature for 28 hours. The THF was removed under reduced pressure. The residue was diluted H ₂ O (1 L) and filtered, washed with H ₂ O until the filtrate became neutral. The product was washed with MeOH to give 50 g of Intermediate 32 .

Step 2: Synthesis of intermediates 33

At 0 ℃, to Intermediate 32 (60.0 g, 186.9 mmol) and _{FeCl 3 (33.0 g, 205.5 mmol} , 1.1 equiv) in THF (600 mL) of the mixture was added _{NaBH 3 CN (29.4 g, 367.1} mmol, 2.5 equivalents). The mixture was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was stopped by the addition of water and the THF was removed in vacuo. It was extracted with DCM (3 x 200 mL). The combined organic phases were washed with H ₂ O and brine, dried and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography to give compound 33 (25.2 g, 42%) and 33A (12.0 g).

LC-MS: </RTI>^< RTI ID=0.0>^</RTI>

¹ H-NMR (CDCl ₃ ): δ: 7.89-7.894 (s, 1H), 7.671-7.696 (d, 1H), 7.311-7.332 (d, 1H), 3.605 (s, 1H), 2.981 (s, 2H) ), 1.769-1.797 (m, 4H), 1.072-1.082 (m, 2H), 1.019-1.056 (m, 6H).

Step 2: Replace the synthetic intermediate 33

So _{FeCl 3 (6.0 g, 37.0 mmol} ) cooled with a mixture of toluene (60 mL) to the 0 ℃. A mixture of compound 32 (11.9 g, 37.0 mmol) in THF (48 mL). The mixture was stirred at 0 °C for 5 minutes and then cooled to -10 °C. A solution of t- BuNH ₂ -BH ₃ (3.5 g, 40.7 mmol) in THF (12 mL) was added dropwise at -10 °C. The reaction mixture was stirred at about -10 °C for 30 minutes, quenched with 6N aqueous HCI (10 mL) and stirred for 30 min. The mixture was concentrated to remove THF and toluene (60 mL). The aqueous layer was removed and the organic phase was washed with water (3×60 mL). The organic phase was concentrated to 1⁄2 volume, heated to 50 ° C to obtain a solution, then cooled to 0 ° C over 1 hour and kept at 0 ° C for 1 hour. The solid was filtered and cold (0 deg.] C) toluene (12 mL) washed, and dried under vacuum to obtain compound 33 (9.93 g, 83%) .

LC-MS: tR = 2.36 min, MS (ESI) m/z 323.0/325.0 [M+H] ⁺

Step 3: Synthesis of intermediates 34

To a mixture of compound 33 (20.0 g, 61.9 mmol) and DMF (200 mL) was added NaH (5.0 g, 123.8 mmol, 2.0 eq.). It was then stirred at 0 °C for 15 minutes and MeI (17.6 g, 123.8 mmol, 2.0 eq.) was added at 0 °C. It was then allowed to warm to room temperature and stirred at room temperature for 1.5 hours. Mixture was quenched in H ₂ O and extracted with EtOAc. The combined organic phases were washed with H ₂ O and brine, dried, and concentrated to give a crude product, which was by silica gel column (eluent: petroleum ether: 100/1 to 5/1 EtOAc) to afford Intermediate 34 (20 g, 96.2%).

Step 4: Synthesis of intermediates 35

A mixture of compound 34 (20.0 g, 59.3 mmol) and ethanol (IV) (108.2 g, 474.4 mmol) in anhydrous THF (200 ml) was stirred for 1 hr. ( S ) -N - T -butylsulfinamide (29 g, 237.2 mmol) was added. The resulting mixture was stirred overnight at 80 ° C under N ₂ atmosphere. The reaction mixture was then cooled and water (400 ml) was added. The mixture was filtered and the aqueous extracted with EtOAc EtOAc The separated organic phase was dried and concentrated under reduced pressure to give a crude material. By silica gel column chromatography (petroleum ether: EtOAc = 20: 1) The residue was purified to give Intermediate 35 (18.4 g, 70.5%) .

Step 5: Synthesis of intermediates 36

At -78 deg.] C, under N ₂ atmosphere, the t -BuLi (131 mL, 170.3 mmol , in hexane of 1.3 M) was added dropwise to ethyl vinyl ether (12.3 g, 170.3 mmol, 5.0 equiv) in The solution in anhydrous THF (100 mL) was stirred for 20 min. The resulting mixture was then stirred at 0 ° C for an additional 45 minutes. The solution was cooled to -78 deg.] C and added dropwise over anhydrous containing compound 35 (15.0 g, 34.1 mmol) of THF (50 mL), and the mixture was stirred at -78 ℃ 2 hours. The reaction mixture with saturated NH ₄ Cl (50 mL) and (3 × 300 mL) and extracted with EtOAc aborted. The organic phase was concentrated to obtain a residue, which was purified by silica gel column chromatography to give Intermediate 36 (11 g, 64.7%) and 36A (1.441 g, 100% purity).

LC-MS </RTI>^< RTI ID=0.0></RTI>^<RTIgt;

¹ H-NMR (CD ₃ OD): δ 7.546 (s, 1H), 7.454-7.479 (d, 1H), 7.208-7.228 (d, 1H), 4.620-4.755 (d, 1H), 4.373-4.381 (m , 1H), 4.048-4.055 (m, 1H), 3.844-3.903 (m, 2H), 3.458-3.474 (s, 3H), 2.986-3.000 (m, 2H), 2.326-2.377 (m, 1H), 1.969 -2.001 (m, 1H), 1.671 (s, 1H), 1.457-1.520 (t, J = 12 Hz, 3H), 1.373-1.408 (m, 2H), 1.328 (s, 9H), 1.169-1.278 (m , 5H), 1.073-1.106 (d, 3H).

Step 5: Synthesis of intermediates 37

The mixture of intermediate 36 (4.8 g, 9.37 mmol) in DCM:MeOH = 5:1 (40 mL) The mixture was then purified to N ₂ and with Me ₂ S (10 mL) treated at -78 ℃, then warmed to room temperature and stirred for 3 hours. The solvent was removed in vacuo, by silica gel column chromatography (petroleum ether: EtOAc = 20: 1 to 8: 1) to give the residue to give 37 (3.5 g, 72.9%) of intermediate.

LC-MS <RTI ID=0.0></RTI> </RTI> <RTIgt;

¹ H NMR (CDCl ₃ ): δ 7.84 (s, 1H), 7.42-7.44 (d, J = 8.0 Hz, 1H), 7.09-7.11 (d, J = 8.0 Hz, 1H), 4.40 (s, 1H) , 4.26-4.39 (m, 2H), 3.44 (s, 3H), 2.93 - 2.97 (d, J = 15.6 Hz, 1H), 2.70 - 2.74 (d, J = 15.2 Hz, 1H), 2.22 - 2.30 (t , J = 10.0 Hz, 1H), 1.75-1.79 (m, 1H), 1.61-1.66 (m, 1H), 1.54-1.57 (m, 2H), 1.32-1.38 (m, 4H), 1.14 (s, 9H) ), 1.06-1.08 (d, J = 6.0 Hz, 3H), 0.89-0.91 (d, J = 6.0 Hz, 3H), 0.67-0.74 (m, 1H).

Step 6: Synthesis of intermediates 38

Add 4 M HCl to a solution of compound 37 (860 mg, 1.7 mmol) in MeOH (10 mL) Solution (2 mL). The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give a crude intermediate 38 (800 mg). The residue was used in the next step without further purification.

Alternative synthetic intermediate 38

Step 1: Synthesis of intermediates 39

A mixture of intermediate 6 (5.00 g, 11.4 mmol), diethoxy acetonitrile (3.5 mL, 24.4 mmol) and THF (50 mL) was cooled to -7 ° C with LDA (25.0 mL, 45.0 mmol, THF/g 1.8 M) of the alkane/ethylbenzene was treated dropwise. The mixture was stirred at -7 to -2 ℃ 2 hours and then water (50 mL) and saturated NH ₄ Cl solution (25 mL) suspension. Hexane (100 mL) was added and the layers were separated. The organic layer was washed with water, brine, and concentrated to obtain a crude intermediate 39 (9.00 g, 139%) , which was used directly in the next step.

LC-MS: tR = 3.74 min, MS (ESI) m/z 523.2/525.2 [M-OEt+H] ⁺

Step 2: Synthesis of intermediates 38

A mixture of the above intermediate 39 (9.00 g, 11.4 mmol) inEtOAc (30 mL) The reaction mixture was heated at 75 ° C for 24 hours and cooled to room temperature. The reaction was extracted with toluene (50 mL) and then aqueous was then basified to pH = 8 using 2N aqueous NaOH (~ 60 mL). Toluene (100 mL) was added and the layers were stirred and separated. The organic layer was washed with aqueous NaHCO ₃ and brine, and concentrated. Hexane was added and the solution was again concentrated to give a crude intermediate 38 (3.47 g, 74%) which was used directly in the next step. LC-MS: tR = 0.86 min, MS (ESI) m/z 410.2/412.2 [M+H] ⁺

Step 7: Synthesis of intermediate 40

Intermediate 40 is synthesized in a manner similar to that described in Step 7 of Intermediate 10A . It is used directly in the next step.

Step 8: Synthesis of intermediates 41

The intermediate 41 is synthesized in a manner similar to that described in the step 8 of the intermediate 11A . The crude intermediate 41 was used directly in the next step.

Step 9: Synthesis of intermediates 42

Intermediate 42 is synthesized in a manner similar to that described in Step 9 of Intermediate 12A . The crude intermediate 42 was used directly in the next step.

Step 10: Synthesis Example 10

42 (400 mg, 0.8 mmol) of the intermediate was in EtOH (8 mL) was added _{NH 3 -H 2 O (1 mL} ) and tert-butyl peroxide (1 mL). After the addition, the mixture was stirred at room temperature for 12 hours. The solvent was removed by evaporation in vacuo. The residue was purified by preparative HPLC method 1 to afford Example 6 (65.0 mg, 20% yield).

_{LC-Ms: t R = 0.945} min, MS (ESI) m / z 463.2 [M + H] +.

¹ H NMR: (CD ₃ OD) δ 8.65-8.70 (s, 2H), 7.60-7.65 (d, J = 7.2 Hz, 1H), 7.45-7.55 (m, 2H), 4.95-5.00 (s, 2H) , 3.40-3.45(s,3H), 3.10-3.20(m,2H), 2.30-2.40(m,1H),1.70-1.80(m,3H),1.45-1.55(m,1H),1.25-1.35 ( m, 2H), 0.90-1.00 (m, 6H).

¹⁹ F NMR (400 MHz, MeOD): -141.57

Example 11

The procedure described in Example 10 of Synthesis Example 11. In Step 9, Example 3 was obtained by using (3-methyloxetan-3-yl)methylamine instead of (5-fluoropyrimidine)-2-methylamine.

_{LC-MS: t R = 0.96} min, MS (ESI) m / z 437 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.75 (dd, J = 7.6, 1.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 6.4 Hz, 2H), 4.32 (dd, J = 8.0, 6.4 Hz, 2H), 3.97 (d, J = 15.6 Hz, 1H), 3.69 (d, J = 15.6 Hz, 1H), 3.44 (s, 3H), 3.25 (m, 2H), 2.44 (t, J = 10.0 Hz, 1H), 1.81-1.75 (m, 2H), 1.67 (m, 1H), 1.41 (s, 3H), 1.36 ( m, 1H), 1.30-1.21 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H).

Example 12

Example 12 was synthesized according to the procedure described in Example 10 . In step 9, Example 12 was obtained using 2-aminooxetane instead of (5-fluoropyrimidine)-2-methylamine.

_{LC-MS: t R = 0.91} min, MS (ESI) m / z 409 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 5.28 (m, 1H), 5.13 (dd, J = 14.0, 6.8 Hz, 2H), 4.87 (dd, J = 8.0, 6.4 Hz, 2H), 3.44 (s, 3H), 3.26 (m, 2H), 2.43 ( t, J = 10.0 Hz, 1H), 1.85-1.77 (m, 2H), 1.68 (m, 1H), 1.35-1.18 (m, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.97 (d) , J = 6.4 Hz, 3H).

Example 13

Example 13 was synthesized according to the procedure described in Example 10 . In Step 9, Example 13 was obtained by using oxetane-3-ylmethylamine instead of (5-fluoropyrimidine)-2methylamine.

_{LC-MS: t R = 0.904} min; MS (ESI) m / z 423.3 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.60-7.62 (d, J = 8.0 Hz, 1H), 7.45-7.47 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 4.69-4.73 ( d, J = 7.2 Hz, 2H), 4.44 - 4.49 (d, J = 7.2 Hz, 2H), 3.85-3.91 (m, 1H), 3.74 - 3.80 (m, 1H), 3.42 (s, 3H), 3.34 -3.38 (m, 1H), 3.08-3.22 (m, 2H), 2.32 - 2.37 (t, J = 10.0 Hz, 1H), 1.61-1.71 (m, 3H), 1.38 (m, 1H), 1.19-1.23 (m, 1H), 0.92-0.99 (m, 7H).

Example 14

Example 14 was synthesized according to the procedure described in Example 10 . In Step 9, Example 14 was obtained by using (S)-2-(aminomethyl)-tetrahydrofuran instead of (5-fluoropyrimidine)-2-methylamine. _{LC-MS: t R = 1.02} min, MS (ESI) m / z 437 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.75 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.35 (s, 1H), 4.16 (m, 1H), 3.96 (m, 1H), 3.83 (m, 1H), 3.70 (m, 2H), 3.50 (s, 3H), 3.30 (d, J = 15.6 Hz, 1H), 3.19 (d, J = 15.6 Hz, 1H) , 2.42 (t, J = 10.0 Hz, 1H), 2.08-1.95 (m, 3H), 1.88-1.1.63 (m, 4H), 1.55 (m, 1H), 1.40-1.30 (m, 2H), 1.05 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H).

Example 15

The procedure described in Example 10 of Synthesis Example 15. In Step 9, Example 15 was obtained by using ( R )-2-(aminomethyl)-tetrahydrofuran instead of (5-fluoropyrimidine)-2-methylamine. _{LC-MS: t R = 1.02} min, MS (ESI) m / z 437 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.61 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 4.07 (m 1H), 3.88 ( m,1H), 3.73 (m,1H), 3.66 (dd, J = 14.8, 3.2 Hz, 1H), 3.57 (dd, J = 14.8, 6.8 Hz, 1H), 3.42 (s, 3H), 3.23 (d , J=16.0 Hz, 1H), 3.10 (d, 16.0 Hz, 1H), 2.35 (t, J = 10.4 Hz, 1H), 2.01-1.86 (m, 3H), 1.76-1.50 (m, 4H), 1.44 (t, J = 13.2 Hz, 1H), 1.24 (m, 1H), 1.03 (t, J = 12.8 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz) , 1H).

Example 16

Example 16 was synthesized according to the procedure described in Example 10 . In step 9, using 2- (aminomethyl) - tetrahydropyran instead of (5-fluoro-pyrimidin) -2-methylamine obtained in Example 16.

_{LC-MS: t R = 0.958} min, MS (ESI) m / z 451.3 [M + H] +.

¹ H NMR (CD ₃ OD): δ 7.62- 1.65 (d, J = 7.6 Hz, 1H), 7.48-7.50 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 3.93-3.96 (m) , 2H), 3.37-3.45 (m, 7H), 3.23 - 3.27 (d, J = 16.0 Hz, 1H), 3.11-3.15 (d, J = 16.0 Hz, 1H), 2.35-2.40 (t, J = 10.0 Hz, 1H), 1.96-2.03 (m, 1H), 1.53-1.80 (m, 5H), 1.23-1.46 (m, 4H), 0.92-1.08 (m, 7H).

Example 17

Example 17 was synthesized according to the procedure described in Example 10 . In step 9, Example 17 was obtained using Intermediate 18 instead of (5-fluoropyrimidine)-2-methylamine.

_{LC-MS: t R = 0.969} min, MS (ESI) m / z 427.2 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.63-7.65 (d, J = 8.0 Hz, 1H), 7.49-7.51 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 3.70-3.76 ( m, 2H), 3.45 (s, 3H), 3.13 - 3.28 (m, 2H), 2.36 - 2.41 (t, J = 10.0 Hz, 1H), 1.65-1.84 (m, 3H), 1.48-1.51 (m, 1H), 1.37-1.42 (m, 6H), 1.26-1.33 (m, 1H), 1.02-1.09 (m, 1H), 0.92-1.00 (m, 6H). ¹⁹ F NMR: (CD ₃ OD): δ - 139.58.

Example 18

Step 9: Synthesis of intermediates 43

Add compound 2-(2-aminomethyl)oxetane (262 mg, 3.01 mmol) and triethylamine (760) to a solution of compound 41 (1 g, 2.51 mmol) in THF (25 mL) Mg, 7.53 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (2 × 35 mL) and brine (2 × 35 mL) in EtOAc (45 mL), followed by. After drying, the solvent was removed to give crude compound 43 and 43A which was purified according to SFC-Method A. The diastereomers were separated by SFC-method B. The desired diastereomer 43 as the second peak is isolated under these conditions. It was further processed as described in step 10 of Example 10 to obtain Example 18 .

_{LC-MS: t R = 0.863} min, MS (ESI) m / z 423.1 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.61-7.63 (d, J = 8.0 Hz, 1H), 7.47-7.49 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 4.95-5.01 ( m, 1H), 4.65-4.70 (m, 1H), 4.52-4.58 (m, 1H), 3.73-3.85 (m, 2H), 3.43 (s, 3H), 3.22-3.26 (d, J = 16.0 Hz, 1H), 3.10-3.14 (d, J = 16.4 Hz, 1H), 2.64-2.72 (m, 1H), 2.33-2.45 (m, 2H), 1.59-1.76 (m, 3H), 1.40-1.49 (m, 1H), 1.22-1.27 (m, 1H), 0.93-1.07 (m, 7H).

Example 19

Synthesis of 3-((2-amino)ethyl)oxetane

Step 1: Synthesis of intermediate 44

2-(Triphenylphosphine)acetonitrile (1.8 g, 6 mmol) was added to EtOAc (EtOAc m. Thereafter, the solvent was removed under reduced pressure to obtain a crude product (260 mg, crude), which Jie silica gel chromatography (petroleum: EtOAc, 3: 1) to afford a white solid of Intermediate 44 (260 mg, Yield 46%).

Step 2: Synthesis of intermediates 45

Niney nickel (Raney-Ni) (100 mg) was added to a mixture of intermediate 44 (260 mg, 2.74 mmol) in MeOH (10 mL). The mixture was then filtered through a pad of Celite ^®. The filtrate was concentrated to give intermediate 45 (200 mg, crude material).

Example 19

Example 19 was synthesized according to the procedure described in Example 10 . In step 9, Example 19 was obtained using Intermediate 45 .

<RTI ID=0.0></RTI>^</RTI>^< RTI ID=0.0></RTI>

¹ H NMR: (CD ₃ OD): δ 7.64-7.66 (d, 1H), 7.49-7.51 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 4.74 - 4.79 (d, 2H), 4.40-4.43 (d, 2H), 3.49-3.52 (m, 2H), 3.45 (s, 3H), 2.95-3.27 (m, 3H), 2.36-2.41 (m, 1H), 1.97-2.05 (m, 2H) ), 1.21-1.80 (m, 5H), 1.01-1.09 (m, 4H), 0.92-0.99 (m, 3H).

Example 20

Step 1: Synthesis of intermediate 46

To a solution of compound 41 (100 mg, 0.25 mmol) in dry EtOAc (3 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by EtOAc (2 <RTI ID=0.0> The combined organic layers were dried and evaporated in vacuo. The crude material was purified by preparative TLC to afford compound 46 (50 mg, 24%).

Step 2: Synthesis of intermediates 47

To a solution of compound 46 (50 mg, 0.118 mmol) in toluene (3 mL), ethyl acetate (0.03 mL) and p-toluenesulfonic acid (1.1 mg, 0.0068 mmol). The solution was heated to reflux for 2 days. The reaction mixture was cooled to room temperature and brine (3 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried and evaporated in vacuo. The crude material was purified by preparative TLC to afford compound 47 (51 mg, %).

Step 3: Synthesis Example 20

To a mixture of compound 47 (51 mg, 0.113 mmol) in MeOH (EtOAc) (EtOAc) The mixture was stirred overnight at room temperature. Saturated Na ₂ S ₂ O ₃ (2.5 mL) was then added to quench the reaction. The mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried and evaporated in vacuo. By substantially purified by preparative HPLC The crude material obtained in Example as a white solid of 20 (12.8 mg, 25%) .

1H-NMR (CD3OD): δ 7.60 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H), 3.86-4.01 (m, 4H), 3.64 3.75 (m, 2H), 3.42 (s, 3H), 3.03-3.23 (m, 2H), 2.34 (t, 1H), 1.61-1.84 (m, 3H), 1.43 (s, 1H), 1.20-1.37 ( m, 4H), 0.89-1.08 (m, 7H).

LC-MS tR = 0.891 min, MS (ESI) m ^.

Example 21

Example 21 was synthesized according to the procedure described in Example 10 . In step 9, use (R)-(1,4-two Example 21 was obtained from 2-yl)methylamine.

_{LC-MS: t R = 0.928} min, MS (ESI) m / z 453.3 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.63-7.61 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.48 (d, 1H), 7.3 (s, 1H), 3.6-3.8 (m, 6H) , 3.6-3.5 (m, 2H), 3.45 (s, 3H), 3.3-3.1 (m, 3H), 2.4 (m, 1H), 1.8-1.6 (m, 3H), 1.6-1.4 (m, 1H) , 1.3-1.2 (m 1H), 1.1 (m, 1H), 0.9-1.01 (m, 6H).

Example 22

Example 22 was synthesized according to the procedure described in Example 10 . In step 9, use (S)-(1,4-two Example 22 was obtained by substituting methyl-2-amine for (5-fluoropyrimidine)-2-methylamine.

_{LC-MS: t R = 0.928} min, MS (ESI) m / z 453.3 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.63-7.61 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.48 (d, 1H), 7.3 (s, 1H), 3.6-3.8 (m, 6H) , 3.6-3.5 (m, 2H), 3.45 (s, 3H), 3.3-3.1 (m, 3H), 2.4 (m, 1H), 1.8-1.6 (m, 3H), 1.6-1.4 (m, 1H) , 1.3-1.2 (m 1H), 1.1 (m, 1H), 0.9-1.01 (m, 6H).

Example 23

Example 23 was synthesized according to the procedure described in Example 10 . In step 9, Example 23 was obtained using Intermediate 25 .

LC-MS: </RTI>^< RTI ID=0.0>^</RTI>

¹ H NMR: (CD ₃ OD): δ 7.62 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 3.88-3.79 (m, 3H) , 3.73-3.62 (m, 3H), 3.43 (s, 3H), 3.25-3.09 (m, 2H), 2.36 (t, 1H), 1.81-1.60 (m, 7H), 1.46 (m, 1H), 1.23 (m, 1H), 1.06 (m, 1H), 0.99-0.92 (m, 6H). ¹⁹ F NMR: (CD ₃ OD 400 MHz): δ - 160.19.

Example 24

Example 24 was synthesized according to the procedure described in Example 10 . In step 9, Example 24 was obtained using 3-pyrimidinyl-methylamine instead of (5-fluoropyrimidine)-2-methylamine.

_{LC-MS: t R = 0.867} min, MS (ESI) m / z 445.1 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 9.08 (s, 1H), 8.74 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.48 (m, 3H), 4.90 (s, 2H), 3.46 (s, 3H), 3.12-3.24 (m, 2H), 2.41 (m, 1H), 1.63-1.75 (m, 3H), 1.49 (m, 1H), 1.28 (m, 2H) ), 1.02 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H).

Example 25

Example 25 was synthesized in a similar manner to Example 18 . In step 9, the two diastereomers were separated using (tetrahydrofuran-3-yl)methylamine and by SFC-method B. The intermediate produced by the second peak of SFC-method B was further processed to obtain Example 26 .

LCMS: tR = 0.845 min; m / z 430.3 [M + H] +.

¹ H NMR: (CD ₃ OD): δ 7.63-7.66 (m, 1H), 7.49-7.51 (m, 1H), 7.31 (s, 1H), 3.84-3.93 (m, 1H), 3.71-3.81 (m) , 2H), 3.48-3.63 (m, 3H), 3.43 (s, 3H), 3.11-3.31 (m, 2H), 2.51-2.78 (m, 2H), 1.22-2.09 (m, 7H), 1.00-1.06 (m, 4H), 0.93-0.99 (m, 3H).

Example 26

Example 26 was synthesized in a similar manner to Example 1 . In the synthesis of Example 28 , Step 1 of Example 1, methyl methacrylate was used in place of methyl acrylate. In step 3, the corresponding polar isomer 6B was isolated and further processed as described in Example 1 . In step 9, Example 28 is obtained using the intermediate 17 .

_{LC-MS: t R = 1.16} min, MS (ESI) m / z 441 [M + H] +.

¹ H NMR (CD ₃ OD): δ 7.64 (dd, 1H, J = 8, 2 Hz), 7.50 (d, 1H, J = 8 Hz), 7.30 (s, 1H), 3.73 (dd, 2H, J=22,4 Hz), 3.44(s,3H), 3.19(ap q,2H,J=16 Hz), 2.49(t,1H,J=10 Hz),1.82-1.72(m,2H),1.71 -1.63 (m, 1H), 1.55 (m, 1H), 1.42-1.33 (m, 8H), 1.22-1.12 (m, 1H), 1.08 (t, 1H, J = 13 Hz), 1.01 (d, 3H) , J = 6 Hz), 0.79 (t, 3H, J = 7 Hz).

Example 27

6 in the synthesis method of Example 27 by Examples. Used in step 9 (1,4-two 2-yl)methylamine, followed by oxidation as described in step 10, gave Example 27.

LC-MS: tR = 0.68 min, MS (ESI) m ^.

¹ H NMR: (CD ₃ OD, 400 MHz) δ 7.67 (unresolved, 1H), 7.48 (d, 1H), 7.20 (unresolved, 1H), 6.66 (s, 2H), 3.78-2.97 (m, 14H) ), 2.59 (m, 1H), 1.92 (m, 1H), 1.66 (m, 2H), 1.42 (m, 1H), 1.28-1.03 (m, 2H), 0.89 (d, 3H), 0.88 (m, 1H)

Example 28

In accordance with the same procedures as in Example 1 and using S -2- (aminomethyl) in two steps of Example 19 Example 28 was synthesized from Intermediate 11B of Example 1 .

LC-MS: tR=0.894 min, MS (ESI) m ^.

¹ H NMR: (CD3OD): δ 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 3.61-3.85 (m, 8H) , 3.58 (s, 3H), 3.56 (s, 1H), 3.17 (m, 2H), 2.77-2.82 (m, 1H), 2.10-2.17 (m, 1H), 1.85-1.88 (m, 1H), 1.69 -1.75 (m, 1H), 1.37-1.45 (m, 3H), 1.24-1.34 (m, 2H), 1.09-1.15 (m, 1H), 0.75 (t, J = 7.6 Hz, 3H).

Example 29

Example 29 was synthesized in a similar manner to Example 20 using 6-fluoro-3-indanone as the starting material.

_{LC-MS t R = 1.02 min} ; MS (ESI) m / z 446 [M + H] +.

¹ H NMR (CD ₃ OD): δ 7.26 (dd, J = 8.4, 5.2 Hz, 1H), 6.95 (m, 1H), 6.62 (dd, J = 8.4, 2.4 Hz, 1H), 4.02-3.89 (m) , 4H), 3.70 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 14.8 Hz, 1H), 3.42 (s, 3H), 3.12 (d, J = 15.2 Hz, 1H), 2.98 (d) , J = 15.2 Hz, 1H), 2.34 (t, J = 10.0 Hz, 1H), 1.79-1.60 (m, 3H), 1.43 (m, 1H), 1.34 (m, 1H), 1.32 (m, 1H) , 1.30 (s, 3H), 1.00 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H).

Claims (14)

A compound represented by a structural formula selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. A pharmaceutical composition comprising at least one compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a BACE1-mediated condition or disease. A compound or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein the BACE1-mediated condition or disease is selected from the group consisting of a neurodegenerative disorder, cognitive decline, cognitive impairment, dementia, and characteristics. A disease that produces beta-like starch deposition or neurofibrillary tangles. A compound or a pharmaceutically acceptable salt thereof for use according to item 5 of the scope of the patent application, wherein the condition or disease is selected from the group consisting of: Alzheimer's disease, chromosome 21 Disease (Down Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), Alzheimer's disease, cerebral amylovascular disease, degenerative Dementia, mixed blood vessels and degenerative dementia, dementia associated with Parkinson's disease, dementia associated with progressive nuclear paralysis, dementia associated with cortical basal degeneration, diffuse Lewy body Az Diffuse Lewy body type of Alzheimer's disease, dry age-related macular degeneration (AMD), and glaucoma. A compound or a pharmaceutically acceptable salt thereof for use according to item 6 of the scope of the patent application, wherein the condition or disease is Alzheimer's disease. A compound or a pharmaceutically acceptable salt thereof for use according to item 6 of the scope of the patent application, wherein the condition or disease is glaucoma. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a BACE1-mediated condition in an individual. The use of a compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the BACE1 mediated disease or condition is selected from the group consisting of a neurodegenerative disorder, cognitive decline, cognitive impairment, dementia And the characteristic is a disease that produces β-type starch deposition or neurofibrillary tangles. The use of a compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the condition or disease is selected from the group consisting of Alzheimer's disease, chromosome 21 trisomy (Tang Hereditary cerebral hemorrhage (HCHWA-D), senile dementia, cerebral amylovascular disease, degenerative dementia, mixed blood vessels and degenerative dementia, associated with Parkinson's disease Dementia, dementia associated with progressive nuclear paralysis, dementia associated with cortical basal ganglia degeneration, diffuse Lewy body type Alzheimer's disease, dry age-related macular degeneration (AMD), and glaucoma. The use of a compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is Alzheimer's disease. The use of a compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is glaucoma. A compound selected from the group consisting of: and Or its salt.